The goal of this Project is to identify a subset of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA) who are currently asymptomatic but who demonstrate both genotypic and phenotypic characteristics that are highly predictive of the development of RA within 3-5 years. We believe that identifying and further characterizing this very high risk population is key to the future goal of developing a primary prevention strategy that would target those individuals for therapeutic intervention prior to the onset of clinically active RA. As part of a funded R01, over the next five years we will finish enrolling and fully evaluating 2100 FDRs of probands with RA. Based on preliminary data, we expect to find a substantial number of FDRs who exhibit patterns of RA-related autoantibodies associated with progression to RA but who do not yet have clinically active disease. From the probands as well as these FDRs, we will also obtain biologic samples that can be used for DNA and other biomarker analysis. We are funded in that R01 to perform RA-related autoantibody and HLA-DR shared epitope analysis, and to re-evaluate FDRs serially in order to follow clinical phenotypes and obtain serial biologic samples. Because of the study design, FDRs can also be readily stratified for the new studies we propose herein by clinical phenotype, RA shared epitope or other genotype, and autoantibody status. Based on additional preliminary data, we expect to find, using both cross sectional and serial analyses, that the RA-associated autoantibody positive FDR group can be further divided into a population that does not exhibit additional biomarkers that are very likely to be associated with progression to clinically active RA, and a population that does exhibit such features of progression. We also expect to find evidence of B and T cell dysfunction in unaffected FDRs who exhibit RArelated autoantibodies and will have a unique opportunity to detect pathogenic T cell epitopes. To accomplish these goals, we propose the following Specific Aims: Specific Aim #1: Determine the proportion of asymptomatic autoantibody-positive FDRs who also exhibit additional biomarkers typically found in patients with active RA. Specific Aim #2: Determine in asymptomatic FDRs the relationships of RA-related autoantibodies and biomarkers to the presence of specific genetic alleles and HLA haplotypes that are associated with the classification of active RA. Specific Aim #3: Examine FDRs who exhibit RA-related autoantibodies for the presence of dysregulated B and T cell immune responses to RA-related autoantigens.